Interventions After First Post-Transplant Cutaneous Squamous Cell Carcinoma: A Proposed Decision Framework.
Cutaneous squamous cell carcinoma (CSCC) is a major cause of morbidity and mortality after organ transplant. Many patients subsequently develop multiple CSCC following a first CSCC, and the risk of metastasis and death is significantly increased compared to the general population. Post-transplant CSCC represents a disease at the interface of dermatology and transplant medicine. Both systemic chemoprevention and modulation of immunosuppression are frequently employed in patients with multiple CSCC, yet there is little consensus on their use after first CSCC to reduce risk of subsequent tumors. While relatively few controlled trials have been undertaken, extrapolation of observational data suggests the most effective interventions may be at the time of first CSCC. We review the need for intervention after a first post-transplant CSCC and evidence for use of various approaches as secondary prevention, before discussing barriers preventing engagement with this approach and finally highlight areas for future research. Close collaboration between specialties to ensure prompt deployment of these interventions after a first CSCC may improve patient outcomes.


Laser triangulation: fundamental uncertainty in distance measurement.
We discuss the uncertainty limit in distance sensing by laser triangulation. The uncertainty in distance measurement of laser triangulation sensors and other coherent sensors is limited by speckle noise. Speckle arises because of the coherent illumination in combination with rough surfaces. A minimum limit on the distance uncertainty is derived through speckle statistics. This uncertainty is a function of wavelength, observation aperture, and speckle contrast in the spot image. Surprisingly, it is the same distance uncertainty that we obtained from a single-photon experiment and from Heisenberg's uncertainty principle. Experiments confirm the theory. An uncertainty principle connecting lateral resolution and distance uncertainty is introduced. Design criteria for a sensor with minimum distanc uncertainty are determined: small temporal coherence, small spatial coherence, a large observation aperture.


Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress.
Relatively few clues have been uncovered to elucidate the cell biological role(s) of mammalian ATP2C1 encoding an inwardly directed secretory pathway Ca2+/Mn2+ pump that is ubiquitously expressed. Deficiency of ATP2C1 results in a human disease (Hailey-Hailey), which primarily affects keratinocytes. ATP2C1-encoded protein is detected in the Golgi complex in a calcium-dependent manner. A small interfering RNA causes knockdown of ATP2C1 expression, resulting in defects in both post-translational processing of wild-type thyroglobulin (a secretory glycoprotein) as well as endoplasmic reticulum-associated protein degradation of mutant thyroglobulin, whereas degradation of a nonglycosylated misfolded secretory protein substrate appears unaffected. Knockdown of ATP2C1 is not associated with elevated steady state levels of ER chaperone proteins, nor does it block cellular activation of either the PERK, ATF6, or Ire1/XBP1 portions of the ER stress response. However, deficiency of ATP2C1 renders cells hypersensitive to ER stress. These data point to the important contributions of the Golgi-localized ATP2C1 protein in homeostatic maintenance throughout the secretory pathway.


Viral etiologies of acute respiratory infections among hospitalized Vietnamese children in Ho Chi Minh City, 2004-2008.
The dominant viral etiologies responsible for acute respiratory infections (ARIs) are poorly understood, particularly among hospitalized children in resource-limited tropical countries where morbidity and mortality caused by ARIs are highest. Improved etiological insight is needed to improve clinical management and prevention. We conducted a three-year prospective descriptive study of severe respiratory illness among children from 2 months to 13 years of age within the largest referral hospital for infectious diseases in southern Vietnam. Molecular detection for 15 viral species and subtypes was performed on three types of respiratory specimens (nose, throat swabs and nasopharyngeal aspirates) using a multiplex RT-PCR kit (Seeplex™ RV detection, Seegene) and additional monoplex real-time RT-PCRs. A total of 309 children were enrolled from November 2004 to January 2008. Viruses were identified in 72% (222/309) of cases, including respiratory syncytial virus (24%), influenza virus A and B (17%), human bocavirus (16%), enterovirus (9%), human coronavirus (8%), human metapneumovirus (7%), parainfluenza virus 1-3 (6%), adenovirus (5%), and human rhinovirus A (4%). Co-infections with multiple viruses were detected in 20% (62/309) of patients. When combined, diagnostic yields in nose and throat swabs were similar to nasopharyngeal aspirates. Similar to other parts in the world, RSV and influenza were the predominant viral pathogens detected in Vietnamese hospitalized children. Combined nasal and throat swabs are the specimens of choice for sensitive molecular detection of a broad panel of viral agents. Further research is required to better understand the clinical significance of single versus multiple viral coinfections and to address the role of bacterial (co-)infections involved in severe respiratory illness.


Anti-stress effects of lemon balm-containing foods.
Lemon balm (Melissa officinalis) has been used historically and contemporarily as a modulator of mood and cognitive function, with anxiolytic effects following administration of capsules, coated tablets and topical application. Following a pilot study with lemon balm extract administered as a water based drink, which confirmed absorption of rosmarinic acid effects on mood and cognitive function, we conducted two similar double-blind, placebo-controlled, crossover studies. These evaluated the mood and cognitive effects of a standardised M. officinalis preparation administered in palatable forms in a beverage and in yoghurt. In each study a cohort of healthy young adults' self-rated aspects of mood were measured before and after a multi-tasking framework (MTF) administered one hour and three hours following one of four treatments. Both active lemon balm treatments were generally associated with improvements in mood and/or cognitive performance, though there were some behavioral "costs" at other doses and these effects depended to some degree on the delivery matrix.


VEGFA splicing: divergent isoforms regulate spermatogonial stem cell maintenance.
Despite being well-known for regulating angiogenesis in both normal and tumorigenic environments, vascular endothelial growth factor A (VEGFA) has been recently implicated in male fertility, namely in the maintenance of spermatogonial stem cells (SSC). The VEGFA gene can be spliced into multiple distinct isoforms that are either angiogenic or antiangiogenic in nature. Although studies have demonstrated the alternative splicing of VEGFA, including the divergent roles of the two isoform family types, many investigations do not differentiate between them. Data concerning VEGFA in the mammalian testis are limited, but the various angiogenic isoforms appear to promote seminiferous cord formation and to form a gradient across which cells may migrate. Treatment with either antiangiogenic isoforms of VEGFA or with inhibitors to angiogenic signaling impair these processes. Serendipitously, expression of KDR, the primary receptor for both types of VEGFA isoforms, was observed on male germ cells. These findings led to further investigation of the way that VEGFA elicits avascular functions within testes. Following treatment of donor perinatal male mice with either antiangiogenic VEGFA165b or angiogenic VEGFA164 isoforms, seminiferous tubules were less colonized following transplantation with cells from VEGFA165b-treated donors. Thus, VEGFA165b and possibly other antiangiogenic isoforms of VEGFA reduce SSC number either by promoting premature differentiation, inducing cell death, or by preventing SSC formation. Thus, angiogenic isoforms of VEGFA are hypothesized to promote SSC self-renewal, and the divergent isoforms are thought to balance one another to maintain SSC homeostasis in vivo.


Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming.
Vaccination is a promising strategy to trigger and boost immune responses against cancer or infectious disease. We have designed, synthesized and characterized aliphatic-polyester (poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) to investigate how the nature of protein association (adsorbed versus entrapped) and polymer/surfactant concentrations impact on the generation and modulation of antigen-specific immune responses. The ability of the NP formulations to target dendritic cells (DC), be internalized and activate the T cells was characterized and optimized in vitro and in vivo using markers of DC activation and co-stimulatory molecules. Ovalbumin (OVA) was used as a model antigen in combination with the engraftment of CD4+ and CD8+ T cells, carrying a transgenic OVA-responding T cell receptor (TCR), to trace and characterize the activation of antigen-specific CD4+ and CD8+ lymph node T cells upon NP vaccination. Accordingly, the phenotype and frequency of immune cell stimulation induced by the NP loaded with OVA, isolated or in combination with synthetic unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotide (ODN) motifs, were characterized. DC-NP interactions increased with incubation time, presenting internalization values between 50 and 60% and 30-40%, in vitro and in vivo, respectively. Interestingly, animal immunization with antigen-adsorbed NP up-regulated major histocompatibility complex (MHC) class II (MHCII), while NP entrapping the antigen up-regulated MHCI, suggesting a more efficient cross-presentation. On the other hand, rather surprisingly, the surfactant used in the NP formulation had a major impact on the activation of antigen presenting cells (APC). In fact, DC collected from lymph nodes of animals immunized with NP prepared using poly(vinil alcohol) (PVA), as a surfactant, expressed significantly higher levels of CD86, MHCI and MHCII. In addition, those NP prepared with PVA and co-entrapping OVA and the toll-like receptor (TLR) ligand CpG, induced the most profound antigen-specific T cell response, by both CD4+ and CD8+ T cells, in vivo. Overall, our data reveal the impact of NP composition and surface properties on the type and extension of induced immune responses. Deeper understanding on the NP-immune cell crosstalk can guide the rational development of nano-immunotherapeutic systems with improved and specific therapeutic efficacy and avoiding off-target effects.


Negative Consequences on the Growth, Morphometry, and Community Structure of the Kelp Macrocystis pyrifera (Phaeophyceae, Ochrophyta) by a Short Pollution Pulse of Heavy Metals and PAHs.
The study of pollution effects in the marine environment has become important in recent decades, and the exposure to simultaneous pollutants has become especially relevant. Indeed, the study of key organisms, such as ecosystem engineers, can show a broader view of the effects of pollutants. In this context, we evaluate in situ the effects of a short (7-day) pollution pulse of combined solutions of heavy metals and polycyclic aromatic hydrocarbons (PAHs) (Cu + PAHs, Cd + PAHs, Cu + Cd, and Cu + Cd + PAHs) on the development and morphological features of Macrocystis pyrifera sporophytes over a period of 90 days. Additionally, we determined the effects on the community structure associated with this kelp. This study evidenced a smaller number of blades and a decreased size of blades and holdfasts, as well as the death of individuals exposed to a secondary mix of metals (Cu + Cd) and a tertiary mix of pollutants (Cu + Cd + PAHs). Regarding the effects on the accompanying fauna, low richness and diversity were registered. M. pyrifera grazers, according to the mixture of pollutants, were either absent or diminished. These results show that the pulse of contamination in the early stages of M. pyrifera negatively affects its development and morphometry, as well as its role as an ecosystem engineer, due to a negative alteration in the species composition.


Structure of the Plasmodium-interspersed repeat proteins of the malaria parasite.
The deadly symptoms of malaria occur as Plasmodium parasites replicate within blood cells. Members of several variant surface protein families are expressed on infected blood cell surfaces. Of these, the largest and most ubiquitous are the Plasmodium-interspersed repeat (PIR) proteins, with more than 1,000 variants in some genomes. Their functions are mysterious, but differential pir gene expression associates with acute or chronic infection in a mouse malaria model. The membership of the PIR superfamily, and whether the family includes Plasmodium falciparum variant surface proteins, such as RIFINs and STEVORs, is controversial. Here we reveal the structure of the extracellular domain of a PIR from Plasmodium chabaudi We use structure-guided sequence analysis and molecular modeling to show that this fold is found across PIR proteins from mouse- and human-infective malaria parasites. Moreover, we show that RIFINs and STEVORs are not PIRs. This study provides a structure-guided definition of the PIRs and a molecular framework to understand their evolution.


Five-year results of thoracic endovascular aortic repair with the Zenith TX2.
This trial evaluated thoracic endovascular aortic repair (TEVAR) compared with open surgical repair of descending thoracic aortic aneurysms and large ulcers at 42 international sites. Whereas several studies demonstrate early safety and utility advantages with TEVAR, longer follow-up is important because of concerns about durability of TEVAR. This prospective, nonrandomized study enrolled 160 TEVAR patients treated with the Cook Zenith TX2 and 70 open surgical repair patients. Although follow-up was limited, 5-year mortality rate was similar at 37% for both groups. Aneurysm-related mortality rate was 5.9% with TEVAR compared with 12% with open surgical repair (P = .11). There were no ruptures of the treated aneurysms in either group or open conversions in the TEVAR group. Predefined severe morbidity occurred at a significantly lower rate in TEVAR (21%) compared with open surgical repair (39%; P < .001). Aneurysm growth was seen by core laboratory in 5.9% of patients and endoleak in 5.7% of patients. Secondary intervention rates were similar between TEVAR (8%) and open surgical repair (12%; P = .49) patients. Five-year results indicate similar all-cause mortality and aneurysm-related mortality with TEVAR compared with open repair. There was a persistent reduction of severe complications with TEVAR. Reinterventions occurred with similar frequency. TEVAR with the TX2 is a safe and effective alternative to open surgical repair for the treatment of anatomically suitable descending thoracic aortic aneurysms and ulcers.


Divergent trends in survival and readmission following a hospitalization for heart failure in the Veterans Affairs health care system 2002 to 2006.
This study sought to determine recent trends over time in heart failure hospitalization, patient characteristics, treatment, rehospitalization, and mortality within the Veterans Affairs health care system. Use of recommended therapies for heart failure has increased in the U.S. However, it is unclear to what extent hospitalization rates and the associated mortality have improved. We compared rates of hospitalization for heart failure, 30-day rehospitalization for heart failure, and 30-day mortality following discharge from 2002 to 2006 in the Veterans Affairs Health Care System. Odds ratios for outcome were adjusted for patient diagnoses within the past year, laboratory data, and for clustering of patients within hospitals. We identified 50,125 patients with a first hospitalization for heart failure from 2002 to 2006. Mean age did not change (70 years), but increases were noted for most comorbidities (mean Charlson score increased from 1.72 to 1.89, p < 0.0001). Heart failure admission rates remained constant at about 5 per 1,000 veterans. Mortality at 30 days decreased (7.1% to 5.0%, p < 0.0001), whereas rehospitalization for heart failure at 30 days increased (5.6% to 6.1%, p = 0.11). After adjustment for patient characteristics, the odds ratio for rehospitalization in 2006 (vs. 2002) was 0.54 (95% confidence interval [CI]: 0.47 to 0.61) for mortality, but 1.21 (95% CI: 1.04 to 1.41) for heart failure rehospitalization at 30 days. Recent mortality and rehospitalization rates in the Veterans Affairs Health Care System have trended in opposite directions. These results have implications for using rehospitalization as a measure of quality of care.


Bridging evidence, policy, and practice to strengthen health systems for improved maternal and newborn health in Pakistan.
Policy and decision making should be based on evidence, but translating evidence into policy and practice is often sporadic and slow. It is recognised that the relationship between research and policy uptake is complex and that dissemination of research findings is necessary, but insufficient, for policy uptake. Political, social, and economic context, use of (credible) data and dialogues between and across networks of researchers and policymakers play important roles in evidence uptake. Advocacy is the process of mobilising political and public opinions to achieve specific aims and its role is crucial in mobilising key actors to push for policy uptake. Advocacy and research groups (i.e. those who would like to see research evidence used by policymakers) may use different approaches and tools to stimulate the diffusion of research findings. The use of mass- and social media, communication with study participants, and the involvement of stakeholders at the early stages of research development are examples of the approaches that can be employed to stimulate diffusion of evidence and increase evidence uptake. The Research and Advocacy Fund (RAF) for Maternal and Newborn Health (MNH) worked within the health system context in Pakistan with the aim of espousing the principles of evidence, advocacy, and dissemination to improve MNH outcomes. The articles included in this special issue are outputs of RAF and highlight where RAF's approaches contributed to MNH policy reforms. The papers discuss critical health system issues facing Pakistan, including service delivery components, demand creation, equitable access, transportation interventions for improved referrals, availability of medicines and equipment, and health workforce needs. In addition to these tangible elements, the health system 'software', i.e. the power and the political and social contexts, is also represented in the collection. These articles highlight three considerations for the future: the growing importance of implementation research, the crucial need for participation and ownership, and the recognition that policymaking can be 'informed' by rather than 'based-on' evidence. The future challenge will be to continue the momentum RAF has created and to welcome a new era of health, wealth, and growth for Pakistan.


Search for quark compositeness with the dijet centrality ratio in pp collisions at √s=7 TeV.
A search for quark compositeness in the form of quark contact interactions, based on hadronic jet pairs (dijets) produced in proton-proton collisions at √s=7 TeV, is described. The data sample of the study corresponds to an integrated luminosity of 2.9 pb(-1) collected with the CMS detector at the LHC. The dijet centrality ratio, which quantifies the angular distribution of the dijets, is measured as a function of the invariant mass of the dijet system and is found to agree with the predictions of the standard model. A statistical analysis of the data provides a lower limit on the energy scale of quark contact interactions. The sensitivity of the analysis is such that the expected limit is 2.9 TeV; because the observed value of the centrality ratio at high invariant mass is below the expectation, the observed limit is 4.0 TeV at the 95% confidence level.


Impacts of wetland dieback on carbon dynamics: A comparison between intact and degraded mangroves.
Mangroves are effective blue carbon sinks and are the most carbon rich ecosystems on earth. However, their areal extent has declined by over one-third in recent decades. Degraded mangrove forests result in reduced carbon captured and lead to release of stored carbon into the atmosphere by CO2 emission. The aim of this study was to assess changes in carbon dynamics in a gradually degrading mangrove forest on Bonaire, Dutch Caribbean. Remote sensing techniques were applied to estimate the distribution of intact and degraded mangroves. Forest structure, sediment carbon storage, sediment CO2 effluxes and dissolved organic and inorganic carbon in pore and surface waters across intact and degraded parts were assessed. On average intact mangroves showed 31% sediment organic carbon in the upper 30 cm compared to 20% in degraded mangrove areas. A loss of 1.51 MgCO2 ha-1 yr-1 for degraded sites was calculated. Water samples showed a hypersaline environment in the degraded mangrove area averaging 93 which may have caused mangrove dieback. Sediment CO2 efflux within degraded sites was lower than values from other studies where degradation was caused by clearing or cutting, giving new insights into carbon dynamics in slowly degrading mangrove systems. Results of water samples agreed with previous studies where inorganic carbon outwelled from mangroves might enhance ecosystem connectivity by potentially buffering ocean acidification locally. Wetlands will be impacted by a variety of stressors resulting from a changing climate. Results from this study could inform scientists and stakeholders on how combined stresses, such as climate change with salinity intrusion may impact mangrove's blue carbon sink potential and highlight the need of future comparative studies of intact versus degraded mangrove stands.


Somatization in cross-cultural perspective: a World Health Organization study in primary care.
The purpose of this study was to examine the phenomenon of somatization in different cultures by determining its frequency and correlates in primary care settings in 14 countries. Consecutive primary care patients (N = 25,916) were screened with the 12-item General Health questionnaire, and a stratified sample (N = 5,438) was interviewed with the Composite International Diagnostic Interview. Interviewed patients were also assessed for physical disease burden, self-rated overall health, physician-rated physical health status, number of disability days, and interviewer-rated occupational role functioning. The authors determined center-specific associations with the use of logistic regression analyses in which confounding variables were controlled. ICD-10 defined somatization disorder was relatively uncommon in most primary care settings. A less restrictively defined form was more common. Symptom rates were much higher in South American sites. There was a modest association with low education. Otherwise, frequency of unexplained somatic symptoms did not clearly vary according to geography or level of economic development. Somatizing patients were at elevated risk for self-reported disease burden, negative perception of their health, and comorbid depression and generalized anxiety disorder. Somatization was also commonly associated with disability. Cultures did not differ markedly in the pattern of these associated features. Somatization is a common problem in primary care across cultures and is associated with significant problems and disability.


Protective Effect of Rheum turkestanicum against Cisplatin by Reducing Oxidative Stress in Kidney Tissue.
Cisplatin is used as chemotherapeutic drug in the treatment of some solid tumors. It causes different side effects such as nephrotoxicity because of increasing oxidative stress and reactive oxygen species production. This study was designed to investigate the effect of Rheum turkestanicum on cisplatin-induced nephrotoxicity in rat. Animals were randomly divided into four groups (six each). Group I received normal saline (1mL/day, intraperitoneally [i.p.]). Group II received a single dose of cisplatin (8mg/kg, i.p.). Groups III and IV received extract at doses of 100mg/kg and 200mg/kg, i.p., respectively, for 3 consecutive days, 1h before a single dose of cisplatin only at the first day. Blood samples were taken for measuring the level of urea and creatinine. Furthermore, 24-h urinary factors such as glucose and protein were measured. Histopathological observation was carried out on kidney sections. Statistical analysis was performed using one-way analysis of variance followed by Tukey-Kramer post hoc test for multiple comparisons. Cisplatin increased the lipid peroxidation, serum creatinine, serum urea, urinary glucose, and urinary protein, whereas decreased the content of thiol in kidney. The extract reduced serum creatinine, serum urea, urinary glucose, urinary protein, lipid peroxidation, and increased thiol following cisplatin administration. Histological studies revealed lower lesions in kidney in the extract-treated groups compared to cisplatin-treated one. This research showed the extract has protective effect against cisplatin-induced nephrotoxicity. This observation may be related to antioxidant properties of the extract.


Antibacterial activity and anticancer activity of Rosmarinus officinalis L. essential oil compared to that of its main components.
In this study, Rosmarinus officinalis L. essential oil and three of its main components 1,8-cineole (27.23%), α-pinene (19.43%) and β-pinene (6.71%) were evaluated for their in vitro antibacterial activities and toxicology properties. R. officinalis L. essential oil possessed similar antibacterial activities to α-pinene, and a little bit better than β-pinene, while 1,8-cineole possessed the lowest antibacterial activities. R. officinalis L. essential oil exhibited the strongest cytotoxicity towards three human cancer cells. Its inhibition concentration 50% (IC₅₀) values on SK-OV-3, HO-8910 and Bel-7402 were 0.025‰, 0.076‰ and 0.13‰ (v/v), respectively. The cytotoxicity of all the test samples on SK-OV-3 was significantly stronger than on HO-8910 and Bel-7402. In general, R. officinalis L. essential oil showed greater activity than its components in both antibacterial and anticancer test systems, and the activities were mostly related to their concentrations.


Dose-response relationship between physical activity and mental health: the Scottish Health Survey.
Regular physical activity is thought to be associated with better mental health, although there is a lack of consensus regarding the optimal amount and type of activity to achieve these benefits. The association between mental health and physical activity behaviours was examined among a representative sample of men and women from the Scottish Health Surveys. Self-reported physical activity was measured and the General Health Questionnaire (GHQ-12) was administered in order to obtain information on current mental health. Participants were 19 842 men and women. Risk estimates per category of physical activity sessions per week were calculated using logistic regression models. Psychological distress (based on a score of 4 or more on the GHQ-12) was evident in 3200 participants. Any form of daily physical activity was associated with a lower risk of psychological distress after adjustment for age, gender, social economic group, marital status, body mass index, long-standing illness, smoking and survey year (OR 0.59, 95% CI 0.52 to 0.66, p<0.001). A dose-response relationship was apparent, with moderate reductions in psychological distress with less frequent activity (OR 0.67, 95% CI 0.61 to 0.75). Different types of activities including domestic (housework and gardening), walking and sports were all independently associated with lower odds of psychological distress, although the strongest effects were observed for sports (OR 0.67, 95% CI 0.54 to 0.82). Mental health benefits were observed at a minimal level of at least 20 min/week of any physical activity, although a dose-response pattern was demonstrated with greater risk reduction for activity at a higher volume and/or intensity.


Social Vulnerability and Mental Health Inequalities in the "Syndemic": Call for Action.
Covid-19 is referred to as a "syndemic," i.e., the consequences of the disease are exacerbated by social and economic disparity. Poor housing, unstable work conditions, caste, class, race and gender based inequities and low incomes have a profound effect on mental health and wellbeing. Such disparities are increasing between, among and within countries and are exacerbated by human rights violations, in institution and in society, stigma and discrimination. Social capital can mediate health outcomes, through trust and reciprocity, political participation, and by mental health service systems, which can be coercive or more open to demand of emancipation and freedom. Societal inequalities affect especially vulnerable groups, and Covid itself had a wider impact on the most socially vulnerable and marginalized populations, suffering for structural discrimination and violence. There are complex relations among these social processes and domains, and mental health inequalities and disparity. Participation and engagement of citizens and community organizations is now required in order to achieve a radical transformation in mental health. A Local and Global Action Plan has been launched recently, by a coalition of organizations representing people with lived experience of mental health care; who use services; family members, mental health professionals, policy makers and researchers, such as the International Mental Health Collaborating Network, the World Federation for Mental Health, the World Association for Psychosocial Rehabilitation, the Global Alliance of Mental Illness Advocacy Networks (GAMIAN), The Mental Health Resource Hub in Chennai, India, The Movement for Global Mental Health (MGMH) and others. The Action Plan addresses the need for fundamental change by focusing on social determinants and achieving equity in mental health care. Equally the need for the politics of wellbeing has to be embedded in a system that places mental health within development and social justice paradigm, enhancing core human capabilities and contrasting discriminatory practices. These targets are for people and organizations to adopt locally within their communities and services, and also to indicate possible innovative solutions to Politics. This global endeavor may represent an alternative to the global mental discourse inspired by the traditional biomedical model.


A Stimulatory Role for Cytokinin in the Arbuscular Mycorrhizal Symbiosis of Pea.
The arbuscular mycorrhizal (AM) symbiosis between terrestrial plants and AM fungi is regulated by plant hormones. For most of these, a role has been clearly assigned in this mutualistic interaction; however, there are still contradictory reports for cytokinin (CK). Here, pea plants, the wild type (WT) cv. Sparkle and its mutant E151 (Pssym15), were inoculated with the AM fungus Rhizophagus irregularis. E151 has previously been characterized as possessing high CK levels in non-mycorrhizal (myc-) roots and exhibiting high number of fungal structures in mycorrhizal (myc+) roots. Myc- and myc+ plants were treated 7, 9, and 11 days after inoculation (DAI) with synthetic compounds known to alter CK status. WT plants were treated with a synthetic CK [6-benzylaminopurine (BAP)] or the CK degradation inhibitor INCYDE, whereas E151 plants were treated with the CK receptor antagonist PI-55. At 13 DAI, plant CK content was analyzed by mass spectrometry. The effects of the synthetic compounds on AM colonization were assessed at 28 (WT) or 35 (E151) DAI via a modified magnified intersections method. The only noticeable difference seen between myc- and myc+ plants in terms of CK content was in the levels of nucleotides (NTs). Whereas WT plants responded to fungi by lowering their NT levels, E151 plants did not. Since NTs are thought to be converted into active CK forms, this result suggests that active CKs were synthesized more effectively in WT than in E151. In general, myc+ and myc- WT plants responded similarly to INCYDE by lowering significantly their NT levels and increasing slightly their active CK levels; these responses were less obvious in BAP-treated WT plants. In contrast, the response of E151 plants to PI-55 depended on the plant mycorrhizal status. Whereas treated myc- plants exhibited high NT and low active CK levels, treated myc+ plants displayed low levels of both NTs and active CKs. Moreover, treated WT plants were more colonized than treated E151 plants. We concluded that CKs have a stimulatory role in AM colonization because increased active CK levels were paralleled with increased AM colonization while decreased CK levels corresponded to reduced AM colonization.


Antiphospholipid antibodies in stillbirth.
To compare antiphospholipid antibodies in deliveries with and without stillbirth using a multicenter, population-based case-control study of stillbirths and live births. Maternal sera were assayed for immunoglobulin (Ig)G and IgM anticardiolipin and anti-β2-glycoprotein-I antibodies. Assays were performed in 582 stillbirth deliveries and 1,547 live birth deliveries. Elevated levels of IgG anticardiolipin and IgG anti-β2-glycoprotein-I antibodies were associated with an approximate threefold increased odds of stillbirth (crude odds ratio [OR] 3.43, 95% confidence interval [CI] 1.79-6.60, 3.8% compared with 1.1% and OR 3.17, 95% CI 1.30-7.72, (1.9% compared with 0.6%, respectively) when all deliveries with stillbirth were compared with all deliveries with live birth. When the subset of stillbirths not associated with fetal anomalies or obstetric complications was compared with term live births, elevated IgG anticardiolipin antibodies were associated with stillbirth (5.0% compared with 1.0%; OR 5.30, 95% CI, 2.39-11.76; IgG anti-β2-glycoprotein-I antibodies (1.9% compared with 0.6%) had an OR of 3.00 (95% CI 1.01-8.90) and IgM anticardiolipin antibodies (6.0% compared with 3.0%) had an OR of 2.03 (95% CI 1.09-3.76). Elevated levels of anticardiolipin and anti-β2-glycoprotein-I antibodies were associated with a threefold to fivefold increased odds of stillbirth. Our data support consideration of testing for antiphospholipid antibodies in cases of otherwise unexplained stillbirth. II.


A genomewide admixture mapping panel for Hispanic/Latino populations.
Admixture mapping (AM) is a promising method for the identification of genetic risk factors for complex traits and diseases showing prevalence differences among populations. Efficient application of this method requires the use of a genomewide panel of ancestry-informative markers (AIMs) to infer the population of origin of chromosomal regions in admixed individuals. Genomewide AM panels with markers showing high frequency differences between West African and European populations are already available for disease-gene discovery in African Americans. However, no such a map is yet available for Hispanic/Latino populations, which are the result of two-way admixture between Native American and European populations or of three-way admixture of Native American, European, and West African populations. Here, we report a genomewide AM panel with 2,120 AIMs showing high frequency differences between Native American and European populations. The average intermarker genetic distance is ~1.7 cM. The panel was identified by genotyping, with the Affymetrix GeneChip Human Mapping 500K array, a population sample with European ancestry, a Mesoamerican sample comprising Maya and Nahua from Mexico, and a South American sample comprising Aymara/Quechua from Bolivia and Quechua from Peru. The main criteria for marker selection were both high information content for Native American/European ancestry (measured as the standardized variance of the allele frequencies, also known as "f value") and small frequency differences between the Mesoamerican and South American samples. This genomewide AM panel will make it possible to apply AM approaches in many admixed populations throughout the Americas.


The role of glutamine synthetase and glutamate dehydrogenase in cerebral ammonia homeostasis.
In the brain, glutamine synthetase (GS), which is located predominantly in astrocytes, is largely responsible for the removal of both blood-derived and metabolically generated ammonia. Thus, studies with [(13)N]ammonia have shown that about 25 % of blood-derived ammonia is removed in a single pass through the rat brain and that this ammonia is incorporated primarily into glutamine (amide) in astrocytes. Major pathways for cerebral ammonia generation include the glutaminase reaction and the glutamate dehydrogenase (GDH) reaction. The equilibrium position of the GDH-catalyzed reaction in vitro favors reductive amination of α-ketoglutarate at pH 7.4. Nevertheless, only a small amount of label derived from [(13)N]ammonia in rat brain is incorporated into glutamate and the α-amine of glutamine in vivo. Most likely the cerebral GDH reaction is drawn normally in the direction of glutamate oxidation (ammonia production) by rapid removal of ammonia as glutamine. Linkage of glutamate/α-ketoglutarate-utilizing aminotransferases with the GDH reaction channels excess amino acid nitrogen toward ammonia for glutamine synthesis. At high ammonia levels and/or when GS is inhibited the GDH reaction coupled with glutamate/α-ketoglutarate-linked aminotransferases may, however, promote the flow of ammonia nitrogen toward synthesis of amino acids. Preliminary evidence suggests an important role for the purine nucleotide cycle (PNC) as an additional source of ammonia in neurons (Net reaction: L-Aspartate + GTP + H(2)O → Fumarate + GDP + P(i) + NH(3)) and in the beat cycle of ependyma cilia. The link of the PNC to aminotransferases and GDH/GS and its role in cerebral nitrogen metabolism under both normal and pathological (e.g. hyperammonemic encephalopathy) conditions should be a productive area for future research.


Renal abscess in Papillion-Lefèvre syndrome.
A 5-year-old female with Papillon-Lefèvre syndrome presented with renal mass. A radiological diagnosis of malignancy was made; however, partial nephrectomy revealed granulomatous disease indicative of chronic infection. Although liver abscess is an emerging complication in patient with Papillon-Lefèvre syndrome, this case represents the first renal abscess described in such patients.


Thyroid status of female rhesus monkeys and preliminary information on impact of perchlorate administration.
Thyroid status was assessed in adult female rhesus monkey breeders at the California National Primate Research Center at the beginning of the breeding season. The 95% confidence intervals for thyrotropin (TSH), thyroxine (T(4)) and triiodothyronine (T(3)) (n = 66-80) were similar to those previously reported in smaller samples of macaque monkeys. Based on human criteria, 10 of 80 monkeys (12%) were hypothyroid (TSH > 2.0 µIU/mL). Because hypothyroxinaemia can be a risk factor in pregnancy, T(4) status was compared with past breeding history, breeding outcome for that season and general health records in a subset of 42 breeders. Age, weight and parity did not differ between monkeys in the lowest T(4) quartile as compared with those in the upper three quartiles. However, T(4) concentrations were significantly associated with the number of missed menstrual cycles during the previous breeding season. In additional work, three healthy lactating rhesus monkeys were given three different doses of environmental contaminant and thyroid iodine uptake inhibitor, ammonium perchlorate (0.006, 0.34, 12.8 mg/kg/day, respectively) in food for two weeks. Thyroid status variables (TSH, T(4), T(3), thyroid radioactive iodine uptake) were then measured. In the monkey receiving the highest perchlorate dose, iodine uptake was suppressed relative to baseline. The study shows the availability of tools to study thyroid status in rhesus monkeys, the variability of thyroid status in the breeder colony and the potential ability of environmental factors to influence thyroid status.


Pressure-induced emergence of unusually high-frequency transverse excitations in a liquid alkali metal: Evidence of two types of collective excitations contributing to the transverse dynamics at high pressures.
Unlike phonons in crystals, the collective excitations in liquids cannot be treated as propagation of harmonic displacements of atoms around stable local energy minima. The viscoelasticity of liquids, reflected in transition from the adiabatic to elastic high-frequency speed of sound and in absence of the long-wavelength transverse excitations, results in dispersions of longitudinal (L) and transverse (T) collective excitations essentially different from the typical phonon ones. Practically, nothing is known about the effect of high pressure on the dispersion of collective excitations in liquids, which causes strong changes in liquid structure. Here dispersions of L and T collective excitations in liquid Li in the range of pressures up to 186 GPa were studied by ab initio simulations. Two methodologies for dispersion calculations were used: direct estimation from the peak positions of the L/T current spectral functions and simulation-based calculations of wavenumber-dependent collective eigenmodes. It is found that at ambient pressure, the longitudinal and transverse dynamics are well separated, while at high pressures, the transverse current spectral functions, density of vibrational states, and dispersions of collective excitations yield evidence of two types of propagating modes that contribute strongly to transverse dynamics. Emergence of the unusually high-frequency transverse modes gives evidence of the breakdown of a regular viscoelastic theory of transverse dynamics, which is based on coupling of a single transverse propagating mode with shear relaxation. The explanation of the observed high-frequency shift above the viscoelastic value is given by the presence of another branch of collective excitations. With the pressure increasing, coupling between the two types of collective excitations is rationalized within a proposed extended viscoelastic model of transverse dynamics.


The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer.
Despite the availability of multiple human epidermal growth factor receptor 2-targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1-positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.


The effects of an AIDS education program on the knowledge and attitudes of a physical therapy class.
The purpose of this investigation was to determine the effect of an education unit on physical therapy students' knowledge about acquired immunodeficiency syndrome (AIDS), their attitudes toward patients with AIDS, and their willingness to treat patients who have AIDS. A sample of convenience of 103 entry-level undergraduate junior physical therapy students, aged 20 to 35 years (mean = 22.1, SD = 2.8), from one class at one institution participated in this study. A two-group pretest-posttest with control group delayed-intervention design was used. Subjects were randomly assigned to either a group that received an AIDS education unit (experimental group) or a group that did not receive a special education unit (control group). All subjects were pretested and posttested together with a modified version of the State University of New York at Buffalo School of Nursing AIDS Study Questionnaire. Willingness to treat patients who have AIDS was assessed based on self-report responses. After the pretest of both groups, the experimental group received an AIDS education unit followed by the posttest, whereas the control group received no AIDS education unit before the posttest. The experimental group showed significant improvement of knowledge, attitudes, and willingness to treat patients who have AIDS as a result of the AIDS education unit. The control group showed no significant change or a lowered score and thus a change in a nondesired direction. The results of this study confirm the effectiveness of an AIDS education program for physical therapy students at this institution. Further study of entry-level graduate physical therapy students, licensed physical therapists, and other allied health professionals is needed to determine whether the education of these groups can affect their knowledge and attitudes toward patients with AIDS. Improved knowledge and attitudes of the health care provider with an increased willingness to treat patients who have AIDS ensures these patients will receive optimal and appropriate health care.


Driving with an arm immobilized in a splint: a randomized higher-order crossover trial.
The aim of this study was to determine whether immobilization of an arm has detrimental effects on driving performance. Thirty-six healthy officers-in-training were assigned a sequence of fiberglass splints (left and right-sided above-the-elbow thumb spica and below-the-elbow splints) with use of a randomized higher-order crossover design. Runs were scored on a cone-marked driving course used for officer certification with predetermined passing requirements. Driving time, the number of cones hit per course section, and the cone-adjusted total time (a five-second penalty per hit cone) were recorded. A linear mixed-effect model with random environmental and learning effects for cone-adjusted time analysis was used. Participants rated perceived driving difficulty and safety with each splint, and ratings were compared with the Wilcoxon signed-rank test. Thirty participants completed the entire set of runs. Analysis of total cone-adjusted time revealed a significant performance decrease with the left arm in an above-the-elbow thumb spica splint (average, 22.2 seconds; p < 0.001) and with the left arm in a below-the-elbow splint (average, 16.2; p = 0.007). Analysis of forward-only course sections revealed poorer performance trends with all splints, with the worst performance with the left arm in an above-the-elbow thumb spica splint. Driving with the left arm in an above-the-elbow thumb spica splint had the highest perceived difficulty (median, 8.0) and lowest perceived safety (median, 3.0). Driving performance as measured with a standardized track and scoring system was significantly degraded with splint immobilization of the left arm. Further studies are required to determine the effect of arm immobilization on normal driving conditions.


Egg consumption and risk of heart failure, myocardial infarction, and stroke: results from 2 prospective cohorts.
Some studies have found that egg consumption is associated with a higher risk of ischemic heart disease in patients with diabetes. Epidemiologic studies of egg consumption in relation to risk of heart failure (HF) and stroke types are scarce. The aim of this study was to examine whether egg consumption is associated with incidence of HF, myocardial infarction (MI), or stroke types. In prospective cohorts of 37,766 men (Cohort of Swedish Men) and 32,805 women (Swedish Mammography Cohort) who were free of cardiovascular disease (CVD), egg consumption was assessed at baseline with a food-frequency questionnaire. Incident CVD cases were identified through linkage with the Swedish National Patient and Cause of Death Registers. The data were analyzed with the use of a Cox proportional hazards regression model. During 13 y of follow-up, we ascertained 1628 HFs, 3262 MIs, 2039 ischemic strokes, and 405 hemorrhagic strokes in men and 1207 HFs, 1504 MIs, 1561 ischemic strokes, and 294 hemorrhagic strokes in women. There was no statistically significant association between egg consumption and risk of MI or any stroke type in either men or women or HF in women. In men, consumption of ≤6 eggs/wk was not associated with HF risk; however, daily egg consumption (≥1/d) was associated with a 30% higher risk of HF (RR: 1.30; 95% CI: 1.01, 1.67). Egg consumption was not associated with any CVD outcome in individuals with diabetes. Daily egg consumption was not associated with risk of MI or any stroke type in either men or women or with HF in women. Consumption of eggs ≥1 time/d, but not less frequent consumption, was associated with an elevated risk of HF in men.


Establishment of a cross-European field site network in the ALARM project for assessing large-scale changes in biodiversity.
The field site network (FSN) plays a central role in conducting joint research within all Assessing Large-scale Risks for biodiversity with tested Methods (ALARM) modules and provides a mechanism for integrating research on different topics in ALARM on the same site for measuring multiple impacts on biodiversity. The network covers most European climates and biogeographic regions, from Mediterranean through central European and boreal to subarctic. The project links databases with the European-wide field site network FSN, including geographic information system (GIS)-based information to characterise the test location for ALARM researchers for joint on-site research. Maps are provided in a standardised way and merged with other site-specific information. The application of GIS for these field sites and the information management promotes the use of the FSN for research and to disseminate the results. We conclude that ALARM FSN sites together with other research sites in Europe jointly could be used as a future backbone for research proposals.


TNF-alpha-mediated apoptosis is initiated in caveolae-like domains.
Caveolae-like domains (CLDs) have been hypothesized to mediate apoptosis, since they contain sphingomyelin and initiate the conversion of sphingomyelin to ceramide. To address whether CLDs are directly involved in apoptosis, CLDs from U937 cells were isolated, taking advantage of their detergent insolubility and low density. The CLDs contained alkaline phosphatase as well as many signaling molecules, including Fyn, protein kinase Calpha, Raf-1, phospholipase Cgamma1, and tyrosine phosphoproteins. Immunoblotting and immunofluorescent data showed that TNF receptor 1 colocalized with CD36 in CLDs, suggesting that TNF-alpha-initiated apoptosis occurs in CLDs. When cells were incubated with lipoprotein-deficient medium, the cholesterol concentration was greatly decreased in CLDs but not in other fractions, implying that the CLDs were selectively disrupted. In the CLD-disrupted cells, the surface expression of TNF receptor 1 and CD36 was significantly reduced. Analysis of cellular morphology, percent DNA fragmentation, DNA laddering, and caspase-3 activity showed that TNF-alpha-mediated apoptosis was blocked in CLD-disrupted cells, whereas anti-Fas-mediated apoptosis was not. Since Fas was not found in CLDs of Jurkat cells, apoptosis by Fas ligation might not require CLDs. Taken together, these data strongly imply that TNF-alpha-mediated apoptosis is initiated in CLDs.


A frailty instrument for primary care: findings from the Survey of Health, Ageing and Retirement in Europe (SHARE).
A frailty paradigm would be useful in primary care to identify older people at risk, but appropriate metrics at that level are lacking. We created and validated a simple instrument for frailty screening in Europeans aged ≥50. Our study is based on the first wave of the Survey of Health, Ageing and Retirement in Europe (SHARE, http://www.share-project.org), a large population-based survey conducted in 2004-2005 in twelve European countries. SHARE Wave 1 respondents (17,304 females and 13,811 males). five SHARE variables approximating Fried's frailty definition. Analyses (for each gender): 1) estimation of a discreet factor (DFactor) model based on the frailty variables using LatentGOLD. A single DFactor with three ordered levels or latent classes (i.e. non-frail, pre-frail and frail) was modelled; 2) the latent classes were characterised against a biopsychosocial range of Wave 1 variables; 3) the prospective mortality risk (unadjusted and age-adjusted) for each frailty class was established on those subjects with known mortality status at Wave 2 (2007-2008) (11,384 females and 9,163 males); 4) two web-based calculators were created for easy retrieval of a subject's frailty class given any five measurements. Females: the DFactor model included 15,578 cases (standard R2 = 0.61). All five frailty indicators discriminated well (p < 0.001) between the three classes: non-frail (N = 10,420; 66.9%), pre-frail (N = 4,025; 25.8%), and frail (N = 1,133; 7.3%). Relative to the non-frail class, the age-adjusted Odds Ratio (with 95% Confidence Interval) for mortality at Wave 2 was 2.1 (1.4 - 3.0) in the pre-frail and 4.8 (3.1 - 7.4) in the frail. Males: 12,783 cases (standard R2 = 0.61, all frailty indicators had p < 0.001): non-frail (N = 10,517; 82.3%), pre-frail (N = 1,871; 14.6%), and frail (N = 395; 3.1%); age-adjusted OR (95% CI) for mortality: 3.0 (2.3 - 4.0) in the pre-frail, 6.9 (4.7 - 10.2) in the frail. The SHARE Frailty Instrument has sufficient construct and predictive validity, and is readily and freely accessible via web calculators. To our knowledge, SHARE-FI represents the first European research effort towards a common frailty language at the community level.


Wake up and smell the coffee: caffeine supplementation and exercise performance-an umbrella review of 21 published meta-analyses.
To systematically review, summarise and appraise findings of published meta-analyses that examined the effects of caffeine on exercise performance. Umbrella review. Twelve databases. Meta-analyses that examined the effects of caffeine ingestion on exercise performance. Eleven reviews (with a total of 21 meta-analyses) were included, all being of moderate or high methodological quality (assessed using the Assessing the Methodological Quality of Systematic Reviews 2 checklist). In the meta-analyses, caffeine was ergogenic for aerobic endurance, muscle strength, muscle endurance, power, jumping performance and exercise speed. However, not all analyses provided a definite direction for the effect of caffeine when considering the 95% prediction interval. Using the Grading of Recommendations Assessment, Development and Evaluation criteria the quality of evidence was generally categorised as moderate (with some low to very low quality of evidence). Most individual studies included in the published meta-analyses were conducted among young men. Synthesis of the currently available meta-analyses suggest that caffeine ingestion improves exercise performance in a broad range of exercise tasks. Ergogenic effects of caffeine on muscle endurance, muscle strength, anaerobic power and aerobic endurance were substantiated by moderate quality of evidence coming from moderate-to-high quality systematic reviews. For other outcomes, we found moderate quality reviews that presented evidence of very low or low quality. It seems that the magnitude of the effect of caffeine is generally greater for aerobic as compared with anaerobic exercise. More primary studies should be conducted among women, middle-aged and older adults to improve the generalisability of these findings.


Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: the use of different viral vectors and the effects of injury.
Gene therapy is a technique that may offer advantages over current methods of cytokine delivery to ligaments. To determine if implanted genes could be expressed in normal and injured knee ligaments, the medial collateral ligament and anterior cruciate ligament were studied in 18 rabbits. A retroviral ex vivo technique using allograft medial collateral ligament and anterior cruciate ligament fibroblasts and an adenoviral in vivo technique were compared as methods for delivering the LacZ marker gene to knee ligaments. Bilateral knee surgeries were performed, and the rabbits were equally divided into three groups. Group 1 received the retrovirus and the medial collateral ligament was ruptured, Group 2 received the adenovirus and the medial collateral ligament was ruptured, and Group 3 received the adenovirus and the medial collateral ligament was not injured. The anterior cruciate ligament was not injured in any group. The medial collateral and anterior cruciate ligaments of the right knees received 10(6) allografted, transduced ligament fibroblasts or 10(9) adenovirus particles, whereas the ligaments of the left knee received a similar volume of saline solution only. Equal numbers of rabbits were killed at 10 days, 3 weeks, and 6 weeks following the procedure. Ligament samples were stained with X-gal to detect the expression of the LacZ gene product, beta-galactosidase. LacZ gene expression was evident in ruptured and uninjured medial collateral ligaments as well as in the anterior cruciate ligament. The expression lasted between 10 days and 3 weeks in the medial collateral and anterior cruciate ligaments with use of the retrovirus and between 3 and 6 weeks in the medial collateral ligament and at least 6 weeks in the anterior cruciate ligament with the adenovirus. The length of gene expression in the ruptured and uninjured medial collateral ligaments did not differ. These preliminary studies indicate that gene transfer to normal and injured knee ligaments is possible.


Computer-controlled microcirculatory support system for endothelial cell culture and shearing.
Endothelial cells (ECs) lining the inner lumen of blood vessels are continuously subjected to hemodynamic shear stress, which is known to modify EC morphology and biological activity. This paper describes a self-contained microcirculatory EC culture system that efficiently studies such effects of shear stress on EC alignment and elongation in vitro. The culture system is composed of elastomeric microfluidic cell shearing chambers interfaced with computer-controlled movement of piezoelectric pins on a refreshable Braille display. The flow rate is varied by design of channels that allow for movement of different volumes of fluid per variable-speed pump stroke. The integrated microfluidic valving and pumping system allowed primary EC seeding and differential shearing in multiple compartments to be performed on a single chip. The microfluidic flows caused ECs to align and elongate significantly in the direction of flow according to their exposed levels of shear stress. This microfluidic system overcomes the small flow rates and the inefficiencies of previously described microfluidic and macroscopic systems respectively to conveniently perform parallel studies of EC response to shear stress.


The epidemiology, risk factors, and impact on hospital mortality of status epilepticus after subdural hematoma in the United States.
Subdural hematoma (SDH) is a well described risk factor in the development of Status Epilepticus (SE), however the epidemiology of SE after SDH is unknown. In this study, we sought to determine the epidemiology of SE, the prevalence of risk factors, and impact on hospital mortality using a large administrative dataset. Data was derived from the Nationwide Inpatient Sample from 1988 through 2011. We queried the NIS database for patients older than 18 years, with a diagnosis of SDH and SE. Diagnoses were defined by ICD 9 CM codes 432.1, 852.2, 852.3 and 345.3 for SE. Adjusted incidence rates of admission and prevalence proportions were calculated. Multivariate logistic models were then fitted to assess for the impact of status epilepticus on hospital mortality. Over the 23-year period, we identified more than 1,583,255 admissions with a diagnosis of SDH. The prevalence of SE in this cohort was 0.5% (7,421 admissions). The population adjusted incidence rate of admissions of SDH increased from 13/100,000 in 1988 to 38/100,000 in 2011. The prevalence of SE in SDH, increased from 0.5% in 1988 to 0.7% in 2011. In hospital mortality of patients with SDH and without SE decreased from 17.9% to 10.3% while in hospital mortality of patients with SDH and SE did not statistically change. Mortality increased over the same period (2.3/100,000 in 1988 to 3.9/100.000 in 2011) and the diagnosis of SE increased mortality in this cohort (OR 2.17, p < 0.0001). The risk of SE remained stable throughout the study period, but was higher among older patients, blacks, and in those with respiratory, metabolic, hematological, and renal system dysfunction. Our study demonstrates that the incidence of admissions of SDH is increasing in the United States. Despite a decline in the overall SDH related mortality, SE increased the risk of in-hospital death in patients with a primary diagnosis of SDH.


Recombination rate variation shapes barriers to introgression across butterfly genomes.
Hybridisation and introgression can dramatically alter the relationships among groups of species, leading to phylogenetic discordance across the genome and between populations. Introgression can also erode species differences over time, but selection against introgression at certain loci acts to maintain postmating species barriers. Theory predicts that species barriers made up of many loci throughout the genome should lead to a broad correlation between introgression and recombination rate, which determines the extent to which selection on deleterious foreign alleles will affect neutral alleles at physically linked loci. Here, we describe the variation in genealogical relationships across the genome among three species of Heliconius butterflies: H. melpomene (mel), H. cydno (cyd), and H. timareta (tim), using whole genomes of 92 individuals, and ask whether this variation can be explained by heterogeneous barriers to introgression. We find that species relationships vary predictably at the chromosomal scale. By quantifying recombination rate and admixture proportions, we then show that rates of introgression are predicted by variation in recombination rate. This implies that species barriers are highly polygenic, with selection acting against introgressed alleles across most of the genome. In addition, long chromosomes, which have lower recombination rates, produce stronger barriers on average than short chromosomes. Finally, we find a consistent difference between two species pairs on either side of the Andes, which suggests differences in the architecture of the species barriers. Our findings illustrate how the combined effects of hybridisation, recombination, and natural selection, acting at multitudes of loci over long periods, can dramatically sculpt the phylogenetic relationships among species.


A meta-analytic review of moral licensing.
Moral licensing refers to the effect that when people initially behave in a moral way, they are later more likely to display behaviors that are immoral, unethical, or otherwise problematic. We provide a state-of-the-art overview of moral licensing by conducting a meta-analysis of 91 studies (7,397 participants) that compare a licensing condition with a control condition. Based on this analysis, the magnitude of the moral licensing effect is estimated to be a Cohen's d of 0.31. We tested potential moderators and found that published studies tend to have larger moral licensing effects than unpublished studies. We found no empirical evidence for other moderators that were theorized to be of importance. The effect size estimate implies that studies require many more participants to draw solid conclusions about moral licensing and its possible moderators.


T-786C variation in the promoter sequence of human eNOS gene markedly influences its expression level.
This study investigated the role of the T-786C polymorphism (SNP) in the 5'-flanking sequence of the endothelial nitric oxide synthase gene (eNOS) on its expression level in vascular endothelium with the ultimate goal of shedding more light on the mechanisms by which genetic variations of eNOS might affect the vascular level of nitric oxide (NO). Sequences in the 5'-flanking region of eNOS gene were PCR-amplified using genomic DNA templates isolated from blood samples collected from cardiovascular disease (CVD) patients. Two sequence-versions carrying the same SNP site were used; a short (345 bp) and an extended one (1,594 bp), numbered relative to the translational start site. All sequences were cloned into a promoter-less vector (pGL3-basic), which carries the firefly luciferase gene as a reporter. Genotyping of the T-786C polymorphism was performed using Sanger sequencing of the insert region. Luminescence levels were then recorded 24-48 h after transfecting human endothelial cell line (EA.hy926). Three genotypes were identified in the subject samples; TT, TC, or CC. The highest expression levels associated with the TT genotype, followed by the TC genotype, then the CC genotype. The extended sequence version produced higher expression levels compared to the shorter version. Our results provide evidence that the T allele at the T-786C SNP site of the eNOS gene results in increased expression of the enzyme, and consequently might provide a protective mechanism from CVD. The extended promoter sequence of eNOS resulted in higher expression of the gene, suggesting the presence of some essential binding sites for transcription enhancing proteins.


In vitro interaction between muscle-derived stem cells and nucleus pulposus cells.
Current therapies for intervertebral disc degeneration (IDD) are aimed at treating the clinical symptoms arising from IDD rather than directly treating the underlying problem. Pathophysiology of IDD is characterized by a progressive decrease in proteoglycan content and cell density in the nucleus pulposus (NP). A cell-based therapy is a promising concept that uses various cell types to repopulate the disc in an attempt to slow, stop, or reverse the progressive loss of proteoglycans. Stem cells appear to be an excellent candidate for this purpose, based on their ability to differentiate into various connective tissue lineages. The muscle tissue could serve as a good source of adult stem cells because of its vast abundance through out the human body. To examine the interaction between the nucleus pulposus cells (NPCs) and the muscle-derived stem cells (MDSCs) in vitro. NPCs and MDSCs were cocultured and proteoglycan production and cell proliferation were evaluated. Various ratios of human NPCs were cocultured for 2 weeks with murine MDSCs (transduced with retro/LacZ) in a monolayer culture. Each well contained an admixture of cells with NPC-to-MDSC ratios of 0:100, 25:75, 50:50, 75:25, 100:0. Glycosaminoglycan (GAG) content (1,9 dimethylmethylene blue [DMMB]), newly synthesized proteoglycan ((35)S incorporation), and DNA content were measured, and cultures were stained with 5-bromo-4-chloro-3-indolyl-beta-D-galactosidase (X-Gal) for cell counting. The NPC-to-MDSC ratio of 75:25 resulted in a significant increase in GAG content compared with NPCs alone. All coculture ratios showed increase in GAG content in comparison with MDSC culture alone. In addition, cocultures showed a significant increase in (35)S incorporation normalized to DNA content in comparison with MDSC alone. The data from this study shows a synergistic effect between MDSCs and NPCs resulting in an upregulated proteoglycan synthesis and NPCs proliferation in vitro.


Intravenous and isolated limb perfusion delivery of wild type and a tumor-selective replicating mutant vaccinia virus in nonhuman primates.
In this study we examine the safety, feasibility, and biodistribution of a tumor-selective mutant vaccinia (vvDD) and wild-type WR (vF13) vaccinia after delivery via intradermal or intravenous infection or isolated limb perfusion (ILP) in rhesus macaques. By intradermal inoculation, 10(6) PFU of vvDD caused a minimal skin reaction whereas vF13 caused marked erythema and necrosis with a peak indurated area of 108 cm2. By intravenous delivery, vvDD caused no clinical symptoms of viremia and no viral recovery from tissues, serum, saliva, urine, or feces. In contrast, vF13 caused symptoms of lethargy, anorexia, fever, and signs of viremia. Delivery of vF13 via ILP resulted in numerous cutaneous pox lesions localized solely to the perfused limb with high viral recovery in the perfused skin and muscle. ILP with vvDD resulted in no visible pox lesions and no clinical signs or symptoms of viremia. No long-term toxicity was identified after ILP with 10(9) PFU of vvDD, and no virus was recovered from any tissue, serum, saliva, urine, or fecal sample. These results suggest that vvDD appears to be safe in primates, and thus vvDD should be further investigated for clinical trial in human cancer patients.


Multivalency Enables Dynamic Supramolecular Host-Guest Hydrogel Formation.
Supramolecular and dynamic biomaterials hold promise to recapitulate the time-dependent properties and stimuli-responsiveness of the native extracellular matrix (ECM). Host-guest chemistry is one of the most widely studied supramolecular bonds, yet the binding characteristics of host-guest complexes (β-CD/adamantane) in relevant biomaterials have mostly focused on singular host-guest interactions or nondiscrete multivalent pendent polymers. The stepwise synergistic effect of multivalent host-guest interactions for the formation of dynamic biomaterials remains relatively unreported. In this work, we study how a series of multivalent adamantane (guest) cross-linkers affect the overall binding affinity and ability to form supramolecular networks with alginate-CD (Alg-CD). These binding constants of the multivalent cross-linkers were determined via NMR titrations and showed increases in binding constants occurring with multivalent constructs. The higher multivalent cross-linkers enabled hydrogel formation; furthermore, an increase in binding and gelation was observed with the inclusion of a phenyl spacer to the cross-linker. A preliminary screen shows that only cross-linking Alg-CD with an 8-arm-multivalent guest results in robust gel formation. These cytocompatible hydrogels highlight the importance of multivalent design for dynamically cross-linked hydrogels. These materials hold promise for development toward cell- and small molecule-delivery platforms and allow discrete and fine-tuning of network properties.


Non-housestaff medicine services in academic centers: models and challenges.
Non-housestaff medicine services are growing rapidly in academic medical centers (AMCs), partly driven by efforts to comply with resident duty hour restrictions. Hospitalists have emerged as a solution to providing these services given their commitment to delivering efficient and high-quality care and the field's rapid growth. However, limited evidence is available on designing these services, including the similarities and differences of existing ones. We describe non-housestaff medicine services at 5 AMCs in order to share our experiences and outline important considerations in service development. We discuss common challenges in building and sustaining these models along with local institutional factors that affect decision making. Keys to success include ensuring an equitable system for scheduling and staffing, fostering opportunities for scholarly activities and academic promotion (defining the "academic hospitalist"), and providing compensation that supports recruitment and retention of hospitalists. With further work hour restrictions expected in the future and increased requests for surgical comanagement, the relationship between AMCs and hospitalists will continue to evolve. To succeed in developing hospitalist faculty who follow long careers in hospital medicine, academic leadership must carefully plan for and evaluate the methods of providing these clinical services while expanding on our academic mission.


The Association of Objective and Subjective Vision Impairment With Self-Reported Time Spent in Sedentary Behaviors in Low- and Middle-Income Countries.
There is a scarcity of studies on the relationship between visual impairment (VI) and time spent in sedentary behavior (SB), especially from low- and middle-income countries (LMICs). Thus, we investigated the association of objectively and subjectively measured VI with SB in adults aged ≥18 years across 6 LMICs. Cross-sectional data from the WHO Study on global AGEing and adult health (SAGE) were analyzed. Objective and subjective visual acuity were measured. Information on self-reported SB was also collected. Multivariable multinomial logistic regression analysis was conducted to assess associations with time spent in SB as the outcome. The sample consisted of 42,489 individuals (mean age = 43.8 [14.4] y; 50.1% females). Only severe objective VI (vs no VI) was significantly associated with ≥11 hours per day of SB (vs <4 h/d) (odds ratio = 4.50; 95% confidence interval, 1.57-12.92). Increasing severity of subjective VI was associated with greater odds for ≥8 hours per day of SB (vs <4 h/d) dose dependently. The present study identified an association of both objectively and subjectively measured VI with time spent in SB in adults residing in LMICs, with subjectively measured VI being a stronger predictor of time spent in SB. Targeted interventions to decrease SB especially in those who perceive themselves to have VI are needed in LMICs.


Nuclear and mitochondrial sequence data reveal the major lineages of starlings, mynas and related taxa.
We investigated the phylogenetic relationships among the major lineages of the avian family Sturnidae and their placement within the Muscicapoidea clade using two nuclear (RAG-1 and myoglobin) and one mitochondrial gene (ND2). Among Muscicapoidea, we recovered three clades corresponding to the families Cinclidae, Muscicapidae and Sturnidae (sensu [Sibley, C.G., Monroe Jr., B.L., 1990. Distribution and Taxonomy of Birds of the World. Yale University Press, New Haven, CT]). Within the sturnoid lineage Mimini and Sturnini are sister groups, with Buphagus basal to them. We identified three major lineages of starlings: the Philippine endemic genus Rhabdornis, an Oriental-Australasian clade (genera Scissirostrum, Gracula, Mino, Ampeliceps, Sarcops, Aplonis), and an Afrotropical-Palaearctic clade (all African taxa, Sturnus and Acridotheres). We discuss the biogeographic implications of our findings and suggest an Asiatic origin for this family. The congruence between the age of major clades, estimated by NPRS, and palaeoclimatic data present evidence for the role of climatic changes in shaping present day distribution of the group.


A compact mock circulation loop for the in vitro testing of cardiovascular devices.
In vitro cardiovascular device performance evaluation in a mock circulation loop (MCL) is a necessary step prior to in vivo testing. A MCL that accurately represents the physiology of the cardiovascular system accelerates the assessment of the device's ability to treat pathological conditions. To serve this purpose, a compact MCL measuring 600 × 600 × 600 mm (L × W × H) was constructed in conjunction with a computer mathematical simulation. This approach allowed the effective selection of physical loop characteristics, such as pneumatic drive parameters, to create pressure and flow, and pipe dimensions to replicate the resistance, compliance, and fluid inertia of the native cardiovascular system. The resulting five-element MCL reproduced the physiological hemodynamics of a healthy and failing heart by altering ventricle contractility, vascular resistance/compliance, heart rate, and vascular volume. The effects of interpatient anatomical variability, such as septal defects and valvular disease, were also assessed. Cardiovascular hemodynamic pressures (arterial, venous, atrial, ventricular), flows (systemic, bronchial, pulmonary), and volumes (ventricular, stroke) were analyzed in real time. The objective of this study is to describe the developmental stages of the compact MCL and demonstrate its value as a research tool for the accelerated development of cardiovascular devices.


Effects of mobile phone type signals on calcium levels within human leukaemic T-cells (Jurkat cells).
To test whether exposure to simulated GSM mobile phone signals (915 MHz, 2 W x kg(-1)) influences the concentration of calcium or calcium signalling patterns in a human lymphocyte cell line. The radiofrequency (RF) energy was delivered via a coaxial applicator to a perfused chamber where cells adherent to a thin glass coverslip were imaged by laser scanning confocal microscopy. Cell calcium concentration, estimated from Fluo-3 fluorescence, was monitored over two 10-min periods; control followed by exposed/sham, with exposure status assigned in a blind and randomized fashion. Both continuous wave (CW) and pulsed wave (PW) RF (on both phytohaemagglutanin-activated and unactivated cells) were studied (with an equal number of sham exposures) on 100 cells per category (total 800 cells). No significant changes were noted for the following: regression slope of calcium fluorescence; mean calcium concentration; number of calcium 'spikes' in each 10 min; or mean height of these 'spikes'. The average frequency from Fourier spectra of these periods showed significant alteration in one category only: PW exposure of activated cells. There is no clear indication that RF emissions from mobile phones are associated with any changes in calcium levels or calcium signalling in lymphocytes.


Anaesthetist-provided pre-hospital advanced airway management in children: a descriptive study.
Pre-hospital advanced airway management has been named one of the top-five research priorities in physician-provided pre-hospital critical care. Few studies have been made on paediatric pre-hospital advanced airway management. The aim of this study was to investigate pre-hospital endotracheal intubation success rate in children, first-pass success rates and complications related to pre-hospital advanced airway management in patients younger than 16 years of age treated by pre-hospital critical care teams in the Central Denmark Region (1.3 million inhabitants). A prospective descriptive study based on data collected from eight anaesthetist-staffed pre-hospital critical care teams between February 1st 2011 and November 1st 2012. Primary endpoints were 1) pre-hospital endotracheal intubation success rate in children 2) pre-hospital endotracheal intubation first-pass success rate in children and 3) complications related to prehospital advanced airway management in children. The pre-hospital critical care anaesthetists attempted endotracheal intubation in 25 children, 13 of which were less than 2 years old. In one patient, a neonate (600 g birth weight), endotracheal intubation failed. The patient was managed by uneventful bag-mask ventilation. All other 24 children had their tracheas successfully intubated by the pre-hospital critical care anaesthetists resulting in a pre-hospital endotracheal intubation success rate of 96 %. Overall first pass success-rate was 75 %. In the group of patients younger than 2 years old, first pass success-rate was 54 %. The total rate of airway management related complications such as vomiting, aspiration, accidental intubation of the oesophagus or right main stem bronchus, hypoxia (oxygen saturation < 90 %) or bradycardia (according to age) was 20 % in children younger than 16 years of age and 38 % in children younger than 2 years of age. No deaths, cardiac arrests or severe bradycardia (heart rate <60) occurred in relation to pre-hospital advanced airway management. Compared with the total population of patients receiving pre-hospital advanced airway management in our system, the overall success rate following pre-hospital endotracheal intubations in children is acceptable but the first-pass success rate is low. The complication rates in the paediatric population are higher than in our pre-hospital advanced airway management patient population as a whole. This illustrates that young children may represent a substantial pre-hospital airway management challenge even for experienced pre-hospital critical care anaesthetists. This may influence future training and quality insurance initiatives in paediatric pre-hospital advanced airway management.


A NEED FOR DYNAMIC HEMATOLOGY AND SERUM BIOCHEMISTRY REFERENCE TOOLS: NOVEL USE OF SINE WAVE FUNCTIONS TO PRODUCE SEASONALLY VARYING REFERENCE CURVES IN PLATYPUSES (ORNITHORHYNCHUS ANATINUS).
Seasonal changes in hematology and serum biochemistry results, described by separate reference intervals for different seasons, have been reported in many animals. We developed a novel method to investigate seasonal variation in values and a reference tool (the reference curve) based on sine wave functions that, for suitable variables, represents data more appropriately than a fixed reference interval. We applied these techniques to values observed in blood samples from 126 adult wild platypuses ( Ornithorhynchus anatinus ; 58 females and 68 males). Samples were collected under isoflurane anesthesia from animals captured in the Inglis Catchment in northwest Tasmania. In general, packed cell volume (PCV), red cell count (RCC), and hemoglobin (Hb) values appeared to be lower than those in two studies that previously reported platypus hematology reference intervals. This likely resulted from reduced stress-related splenic contraction or isoflurane-associated splenic sequestration of red blood cells in our study. Reference curves were described for five variables (PCV, RCC, Hb, albumin, and magnesium). We found evidence that this seasonal variation may result from metabolic changes associated with seasonal variations in environmental temperature. These observations suggest that it is important for researchers reporting platypus hematology and serum biochemistry to look for seasonal changes in their data to ensure it is appropriately interpreted.


Approximate Bayesian multibody tracking.
Visual tracking of multiple targets is a challenging problem, especially when efficiency is an issue. Occlusions, if not properly handled, are a major source of failure. Solutions supporting principled occlusion reasoning have been proposed but are yet unpractical for online applications. This paper presents a new solution which effectively manages the trade-off between reliable modeling and computational efficiency. The Hybrid Joint-Separable (HJS) filter is derived from a joint Bayesian formulation of the problem, and shown to be efficient while optimal in terms of compact belief representation. Computational efficiency is achieved by employing a Markov random field approximation to joint dynamics and an incremental algorithm for posterior update with an appearance likelihood that implements a physically-based model of the occlusion process. A particle filter implementation is proposed which achieves accurate tracking during partial occlusions, while in cases of complete occlusion, tracking hypotheses are bound to estimated occlusion volumes. Experiments show that the proposed algorithm is efficient, robust, and able to resolve long-term occlusions between targets with identical appearance.


Three-dimensional echocardiography in a dynamic heart phantom: comparison of five different methods to measure chamber volume using a commercially available software.
Several methods of analysis are available for quantification of left ventricular volumes and ejection fraction using three-dimensional (3D) echocardiography. This study compared the accuracy and reproducibility of five methods of analysis in a novel, irregularly shaped dynamic heart phantom with excellent image quality. Five 3D datasets were acquired on a Philips IE33 platform using an X5-1 3D transducer. Each dataset was analysed by five different methods using the Philips QLab v8.1 software: Methods A1, A2 and A3, semi-automated contour detection with varying degrees of user correction; Method B, Simpson's biplane method using optimally aligned four- and two-chamber views and Method C, method of discs, manually delineated in reconstructed short-axis views. Time-volume curves were generated for each method and compared with the true volumes measured throughout systole in the phantom heart. A second observer repeated measurements by each method in a single 3D dataset. Method A1 (uncorrected semi-automated contouring) produced the most consistent time-volume curves, although end-diastolic and end-systolic volumes varied between datasets. Any manual correction of contours (Methods A2, A3 and B) resulted in significant variation in the time-volume curves, with less consistent endocardial tracking. Method C was not only the most accurate and reproducible method, but also the most time-consuming one. Different methods of 3D volume quantification vary significantly in accuracy and reproducibility using an irregular phantom heart model. Although contouring may appear optimal in long-axis views, this may not be replicated circumferentially, and the resulting measures appeared to be less robust following the manual correction of semi-automated contours.


Yeast glycolytic mRNAs are differentially regulated.
The regulation of glycolytic genes in response to carbon source in the yeast Saccharomyces cerevisiae has been studied. When the relative levels of each glycolytic mRNA were compared during exponential growth on glucose or lactate, the various glycolytic mRNAs were found to be induced to differing extents by glucose. No significant differences in the stabilities of the PFK2, PGK1, PYK1, or PDC1 mRNAs during growth on glucose or lactate were observed. PYK::lacZ and PGK::lacZ fusions were integrated independently into the yeast genome at the ura3 locus. The manner in which these fusions were differentially regulated in response to carbon source was similar to that of their respective wild-type loci. Therefore, the regulation of glycolytic mRNA levels is mediated at the transcriptional level. When the mRNAs are ordered with respect to the glycolytic pathway, two peaks of maximal induction are observed at phosphofructokinase and pyruvate kinase. These enzymes (i) catalyze the two essentially irreversible steps on the pathway, (ii) are the two glycolytic enzymes that are circumvented during gluconeogenesis and hence are specific to glycolysis, and (iii) are encoded by mRNAs that we have shown previously to be coregulated at the translational level in S. cerevisiae (P. A. Moore, A. J. Bettany, and A. J. P. Brown, NATO ASI Ser. Ser. H Cell Biol. 49:421-432, 1990). This differential regulation of glycolytic mRNA levels might therefore have a significant influence upon glycolytic flux in S. cerevisiae.


Acetylsalicylic acid--induced hemolysis and its mechanism.
Acetylsalicylic acid (ASA) is known to cause severe hemolytic anemia in some glucose-6-phosphate-dehydrogenase-deficient (G-6-PD-deficient) individuals. To study its mechanism, erythrocytes from an ASA-sensitive patient were transfused into a normal compatible recipient. The administration of 2,5-dihydroxybenzoic (gentisic) acid, a known ASA metabolite with redox properties, to the recipient resulted in a marked decrease in the survival of the patient's erythrocytes. Similar studies with red cells from individuals with A- and Mediterranean variants of G-6-PD revealed no alteration in the erythrocytes' survival. Further studies disclosed that both salicylate and gentisate competitively inhibited the G-6-PD from the ASA-sensitive patient resulting in a marked change in the K(m) for NADP. These drugs also inhibited the A- and Mediterranean variants of G-6-PD. The magnitude of inhibition, however, was comparatively small and not different from that observed with a normal enzyme. The above studies suggested that enzyme inhibition by salicylate and gentisate may play an important role in ASA-induced hemolysis. Such an inhibition would further curtail NADPH regeneration, rendering the cells more vulnerable to oxidants. In this connection, gentisate seems to play a major role in ASA-induced hemolysis for it is both a G-6-PD inhibitor and an "oxidant."


Rule extraction in gene-disease relationship discovery.
Biomedical data available to researchers and clinicians have increased dramatically over the past years because of the exponential growth of knowledge in medical biology. It is difficult for curators to go through all of the unstructured documents so as to curate the information to the database. Associating genes with diseases is important because it is a fundamental challenge in human health with applications to understanding disease properties and developing new techniques for prevention, diagnosis and therapy. Our study uses the automatic rule-learning approach to gene-disease relationship extraction. We first prepare the experimental corpus from MEDLINE and OMIM. A parser is applied to produce some grammatical information. We then learn all possible rules that discriminate relevant from irrelevant sentences. After that, we compute the scores of the learned rules in order to select rules of interest. As a result, a set of rules is generated. We produce the learned rules automatically from the 1000 positive and 1000 negative sentences. The test set includes 400 sentences composed of 200 positives and 200 negatives. Precision, recall and F-score served as our evaluation metrics. The results reveal that the maximal precision rate is 77.8% and the maximal recall rate is 63.5%. The maximal F-score is 66.9% where the precision rate is 70.6% and the recall rate is 63.5%. We employ the rule-learning approach to extract gene-disease relationships. Our main contributions are to build rules automatically and to support a more complete set of rules than a manually generated one. The experiments show exhilarating results and some improving efforts will be made in the future.


Laser interstitial thermal therapy compared with open resection for treating subependymal giant cell astrocytoma.
Subependymal giant cell astrocytomas (SEGAs) are WHO grade 1 tumors associated with tuberous sclerosis that classically arise from the ventricular wall near the caudate groove and foramen of Monro. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique, which works by heating a stereotactically placed laser fiber to ablative temperatures under MRI thermometry monitoring. In this paper, the authors present LITT as a surgical alternative to open resection of SEGAs. Twelve patients with SEGAs who underwent 16 procedures between 2007 and 2022 at a single institution were retrospectively reviewed. These patients underwent either open resection or LITT. Clinical data, imaging, recurrence rate, further treatments, and related complications were analyzed. Among the 16 procedures, 9 were open resection and 7 were LITT. An external ventricular drain was placed in 66% (6/9) of open procedures and 57.1% (4/7) of LITT cases. A septostomy was performed in 56% (5/9) of open procedures and 29% (2/7) of LITT cases. Complication rates were higher in open cases than in LITT procedures (44% vs 0%, p < 0.05). Complications included hydrocephalus, transient venous ischemia, wound infection, and bone flap migration. The median length of hospital stay was 4 days (IQR 3.3-5.5 days) for open cases and 4 days (IQR 3.0-7.0 days) for LITT procedures. Recurrence or progression occurred after 3 open cases and 2 LITT cases (33% vs 33%, p = 0.803). For the recurrences, 2 open cases underwent stereotactic radiosurgery, 1 open case underwent LITT, and 1 LITT case underwent repeat LITT. Among the LITT cases, only the patients with no decrease in tumor size by 6 months experienced tumor progression afterward. The 2 LITT cases with progression were the only ones with calcification present on preoperative imaging. The median follow-up times for cases assessed for progression were 8.4 years (IQR 3.8-14.4 years) for open resection and 3.9 years (IQR 3.4-5.1 years) for LITT. The small size of this case series limits generalizability or adequate comparison of safety. However, this series adds to the literature supporting LITT as a less invasive surgical alternative to open resection of SEGAs and demonstrates that LITT has similar recurrence and/or progression rates to open resection. Additional studies with more data are necessary for comprehensive comparisons between open resection and LITT for treating SEGA.


Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients.
Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients. To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. Retrospective study. Academic hospital. 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls. TSH, FT4 and FT3 concentrations by immunoassays. FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients. Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.


Small-angle scattering computed tomography (SAS-CT) using a Talbot-Lau interferometerand a rotating anode x-ray tube:theory and experiments.
X-ray differential phase contrast imaging methods, including projection imaging and the corresponding computed tomography (CT), have been implemented using a Talbot interferometer and either a synchrotron beam line or a low brilliance x-ray source generated by a stationary-anode x-ray tube. From small-angle scattering events which occur as an x-ray propagates through a medium, a signal intensity loss can be recorded and analyzed for an understanding of the micro-structures in an image object. This has been demonstrated using a Talbot-Lau interferometer and a stationary-anode x-ray tube. In this paper, theoretical principles and an experimental implementation of the corresponding CT imaging method are presented. First, a line integral is derived from analyzing the cross section of the small-angle scattering events. This method is referred to as small-angle scattering computed tomography (SAS-CT). Next, a Talbot-Lau interferometer and a rotating-anode x-ray tube were used to implement SAS-CT. A physical phantom and human breast tissue sample were used to demonstrate the reconstructed SAS-CT image volumes.


Treatments for Internet gaming disorder and Internet addiction: A systematic review.
Problems related to excessive use of the Internet and video games have recently captured the interests of both researchers and clinicians. The goals of this review are to summarize the literature on treatment effectiveness for these problems and to determine whether any treatments meet the minimum requirement of an evidence-based treatment as defined by Chambless et al. (1998). Studies of treatments for Internet gaming disorder (IGD) and Internet addiction were examined separately, as past studies have linked IGD to more severe outcomes. The systematic review identified 26 studies meeting predefined criteria; 13 focused on treatments for IGD and 13 on Internet addiction. The results highlighted a paucity of well-designed treatment outcome studies and limited evidence for the effectiveness of any treatment modality. Studies were limited by methodological flaws, including small sample sizes, lack of control groups, and little information on treatment adherence, among other problems. In addition, the field is beset by a lack of consistent definitions of and established instruments to measure IGD and Internet addiction. The results of this review highlight the need for additional work in the area of treatment development and evaluation for IGD and Internet addiction. Attention to methodological concerns identified within this review should improve subsequent research related to treating these conditions, and ultimately outcomes of patients suffering from them. (PsycINFO Database Record